Lead optimization and biological evaluation of fragment-based cN-II inhibitors

European Journal of Medicinal Chemistry
Rémi GuillonSuzanne Peyrottes

Abstract

The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200 μM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58 mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies...Continue Reading

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Citations

Nov 30, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Philine KirschMartin Empting
Jan 13, 2021·Biochimica Et Biophysica Acta. General Subjects·Muhammad-Zawwad RazaLars Petter Jordheim
Oct 7, 2021·Nucleosides, Nucleotides & Nucleic Acids·Lars Petter Jordheim

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